Affecting one in 700 live births, Down Syndrome is the major recognized genetic cause of mental retardation. It is, and expected to remain, a significant medical and social problem. While the neurological and behavioral phenotype of Down Syndrome and its genetic basis is complex, recent advances in technology, resources and knowledge mean that renal and effective progress in understanding Down Syndrome is now attainable. The immediate goal of this program project is the identification and characterization of the genes involved in the neurological, neurophysiological and behavioral phenotype of Down Syndrome. The long term goal is to apply this knowledge to the development of therapeutic interventions to ameliorate the cognitive deficits seen in Down Syndrome. The accomplishment of goals of this nature requires application of a broad spectrum of approaches, spanning molecular biology, mouse genetics and human behavior. Accordingly, this proposal will build upon the large body of information regarding Down Syndrome and human chromosome 21 compiled by this Program over the last fifteen years, and will extend its research focus in a clinically relevant direction. The specific aims of this program include: i)systematic identification and preliminary characterization of essentially all genes on chromosome 21 to determine best candidates for causation of the neurological and cognitive deficits of Down Syndrome; ii) construction and analysis of mouse models, both single gene transgenics and segmental trisomies, to test the roles of specific genes; iii) dissection of the cognitive deficits seen in individuals with Down Syndrome; iv) analysis of the behavior and physiology of relevant mouse mutants to refine understanding of the deficits seen in individuals with Down Syndrome and to define the limits of utility of mouse models; and v) design and testing in mice of new hypotheses and treatment approaches based on information obtained from the molecular, human behavior and mouse genetic data. Building on the past accomplishments and expertise of members of this program project and adding new directions and new areas of expertise makes attainment of these goals eminently feasible. Their success will add greatly to our understanding of neurological development in general and of mental retardation in Down syndrome in particular.